ArticlePLoS genetics2021
A novel type of colistin resistance genes selected from random sequence space.
Article in PLoS genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 47 citations in OpenAlex.
- A Reassessment of Positive Growth Effects of Expressed Random Sequence Clones in E. coli Suggests Direct Adaptive Functions.Genome biology and evolution · 2026Article
- Imported, not invented, genes prevail amongProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Colistin Resistance in Gram-Negative Bacteria: Mechanisms, Transmission, and Novel Intervention Strategies.Microorganisms · 2026Review
- Proteome-wide remodelling in Klebsiella pneumoniae during step-wise adaptive evolution against colistin.PloS one · 2026Article
- Something from nothing: The birth of new phage defense genes.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Emergence of antiphage functions from random sequence libraries reveals mechanisms of gene birth.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- De novo gene birth and the conundrum of ORFan genes in bacteria.Genome research · 2025Review
- Antimicrobial peptides: from discovery to developmental applications.Applied and environmental microbiology · 2025Review
- Expression of Random Sequences and de novo Evolved Genes From the Mouse in Human Cells Reveals Functional Diversity and Specificity.Genome biology and evolution · 2024Article
- Large Roles of Small Proteins.Annual review of microbiology · 2024Review
- De Novo Genes.Annual review of genetics · 2024Review
- Sequence, Structure, and Functional Space of Drosophila De Novo Proteins.Genome biology and evolution · 2024Article
- Large-scale investigation of species-specific orphan genes in the human gut microbiome elucidates their evolutionary origins.Genome research · 2024Article
- Potent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid A.Nature communications · 2024Article
- Promoter recruitment drives the emergence of proto-genes in a long-term evolution experiment with Escherichia coli.PLoS biology · 2024Article
- A review of the mechanisms that confer antibiotic resistance in pathotypes ofFrontiers in cellular and infection microbiology · 2024Review
- Selection of a de novo gene that can promote survival of Escherichia coli by modulating protein homeostasis pathways.Nature ecology & evolution · 2023Article
- Toxin rescue by a random sequence.Nature ecology & evolution · 2023Article
- Genomic Insights into Bacterial Resistance to Proline-Rich Antimicrobial Peptide Bac7.Membranes · 2023Article
- Experimental characterization of de novo proteins and their unevolved random-sequence counterparts.Nature ecology & evolution · 2023Article
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6 authors at 2 institutions in 3 countries.
Funding
Abstract
Antibiotic resistance is a rapidly increasing medical problem that severely limits the success of antibiotic treatments, and the identification of resistance determinants is key for surveillance and control of resistance dissemination. Horizontal transfer is the dominant mechanism for spread of resistance genes between bacteria but little is known about the original emergence of resistance genes. Here, we examined experimentally if random sequences can generate novel antibiotic resistance determinants de novo. By utilizing highly diverse expression libraries encoding random sequences to select for open reading frames that confer resistance to the last-resort antibiotic colistin in Escherichia coli, six de novo colistin resistance conferring peptides (Dcr) were identified. The peptides act via direct interactions with the sensor kinase PmrB (also termed BasS in E. coli), causing an activation of the PmrAB two-component system (TCS), modification of the lipid A domain of lipopolysaccharide and subsequent colistin resistance. This kinase-activation was extended to other TCS by generation of chimeric sensor kinases. Our results demonstrate that peptides with novel activities mediated via specific peptide-protein interactions in the transmembrane domain of a sensory transducer can be selected de novo, suggesting that the origination of such peptides from non-coding regions is conceivable. In addition, we identified a novel class of resistance determinants for a key antibiotic that is used as a last resort treatment for several significant pathogens. The high-level resistance provided at low expression levels, absence of significant growth defects and the functionality of Dcr peptides across different genera suggest that this class of peptides could potentially evolve as bona fide resistance determinants in natura.
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